Design And Synthesis Of Endomorphine Tripeptide Compounds

In 1997,Zadina isolsted two tetrapeptides,endomorphin-1(EM-1,Tyr-Pro-TrpPhe-NH2)and endormophine-2(EM-2,Tyr-Pro-Phe-Phe-NH2),from bovine frontal cortex,these two opioid show high affinity and remarkable selective fou ?-opioid receptor.They were reported to be the endogenous ligand to ?-opioid receptors.Endormorphin can produce equivalent analgesia with morphine even in low concentrations,and has less undesirable side effects due to their characteristics of endogenous.But peptides readily undergo metabolic degradation by peptidases and are difficult in transport through the blood-brain barrier(BBB).Therefore,design and synthesize new and improved Ems analogues by chemical modification is a effective way to develop compounds with less side effects and strong analgesic effect.Studies have shown that the first three amino acids of the peptide play an important role in the binding and activation of the receptor.The tripeptide of endomorphin,Dmt-Pro-l-Nal-NH2,is a opioid peptide with a strong mu receptor activity and a delta receptor antagonist properties.Studies have shown that ligands with mixed ?-agonists/?-antagonist exhibit lower tolerance and dependence.In order to further study the structure-activity relationship of endomorphins,based on previous work,we synthesize a series of 1-Nal analogues,7-OH-1-Nal?7-7-CH3O1-Nal?7-EtO-1-Nal?7-CH3-1-Nal.The Dmt-Pro-(7-OH)-1-Nal-NH2?Dmt-Pro-(7OCH3)-1-Nal-NH2?Dmt-Pro-(7-OCH2CH3)-1-Nal-NH2?Dmt-Pro-(7-CH3)-1-NalNH2?Dmt-Pro-(5-Br)-Trp-NH2?Dmt-Pro-(6-Br)-Trp-NH2 series tripeptide compounds were synthesized using these synthetic amino acids and the purchased 5-bromide-Ltryptophan and 6-bromo-L-tryptophan.Study on the stability of plasma in vitro showed that Dmt-Pro-(7-OH)-1-Nal-NH2,Dmt-Pro-(7-OCH3)-1-Nal-NH2,Dmt-Pro(7-CH3)-1-Nal-NH2,Dmt-Pro-(6-Br)-Trp-NH2 half-life were more than 60 min,including Dmt-Pro-(7-OCH3)-1-Nal-NH2 more than 120 min,Dmt-Pro-(6-Br)-TrpNH2 approximately 120 min.Further pharmacological studies are under way.